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Rare mutations in TARDBP, the gene encoding TDP-43, cause amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is seen in a large majority of ALS patients, suggesting a central pathogenic role of this regulatory protein. The consequences of TARDBP mutations on TDP-43 function and the mechanism by which mutant TDP-43 causes neurodegeneration remain uncertain. Here, we characterize a series of knockin mice carrying disease-associated TARDBP mutations. We demonstrate that TDP-43M337V and TDP-43G298S are functional, each rescuing the lethality of TDP-43 loss of function. In a subset of aged heterozygous knockin mice, we observe the earliest signs of selective motor neuron degeneration, demonstrating that physiological levels of mutant TDP-43 are sufficient to initiate disease. Furthermore, aged homozygous mutants develop selective, asymmetric motor neuron pathology, providing in vivo evidence of TDP-43 dose-dependent neurotoxicity. These knockin mice represent a faithful in vivo model of early-stage ALS and enable future exploration of TDP-43-associated neurodegeneration.
Pubmed ID: 30625319
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This polyclonal secondary targets IgG (H+L)
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View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets TDP-43
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View all literature mentionsThis unknown targets Rabbit IgG (H+L)
View all literature mentionsThis polyclonal targets Rabbit Synaptophysin
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